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Am J Physiol Gastrointest Liver Physiol (October 7, 2004). doi:10.1152/ajpgi.00316.2004
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Submitted on July 16, 2004
Accepted on October 1, 2004

CATHEPSIN B INACTIVATION ATTENUATES HEPATOCYTE APOPTOSIS AND LIVER DAMAGE IN STEATOTIC LIVERS AFTER COLD ISCHEMIA/WARM REPERFUSION INJURY

E. S. Baskin-Bey1, A. Canbay1, S. F. Bronk1, N. Werneburg1, M. E. Guicciardi1, S. L. Nyberg1, and G. J. Gores1*

1 Mayo Clinic College of Medicine, Rochester, MN, USA

* To whom correspondence should be addressed. E-mail: gores.gregory{at}mayo.edu.

Hepatic steatosis predisposes the liver to cold ischemia/warm reperfusion injury (CI/WR) by unclear mechanisms. Because hepatic steatosis has recently been associated with a lysosomal pathway of apoptosis, our aim was to determine if this cell death pathway contributes to CI/WR injury of steatotic livers. Wild-type and cathepsin Bknockout (Ctsb-/-) mice were fed the methionine/choline deficient (MCD) diet for 2 weeks to induce hepatic steatosis. Mouse livers were stored in the University of Wisconsin (UW) solution for 24 hrs at 4°C and reperfused for 1 hr at 37°C in vitro. Immunofluorescence analysis of the lysosomal enzymes, cathepsin B and D, showed a punctated intracellular pattern consistent with lysosomal localization in wild-type mice fed a standard diet after CI/WR injury. In contrast, cathepsin B and D fluorescence became diffuse in livers from wild-type mice fed MCD diet after CI/WR, indicating that lysosomal permeabilization had occurred. Hepatocyte apoptosis was rare in both normal and steatotic livers in the absence of CI/WR injury, but increased in wild-type mice fed a MCD diet and subjected to CI/WR injury. In contrast, hepatocyte apoptosis and liver damage were reduced in Ctsb-/- and cathepsin B inhibitor treated mice fed the MCD diet following CI/WR injury. In conclusion, these findings support a prominent role for the lysosomal pathway of apoptosis in steatotic livers following CI/WR injury.




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